Pregnancy has long presented scientists with a paradox: A mother's immune system should attack any foreign tissue, and her developing child is just that--because it bears some of its father's genetic material. So why don't all pregnancies end in miscarriage, just as many organ transplants ultimately meet with rejection?

Image: HECTOR D. MOLINA

NORMAL EMBRYO. A nine-day-old mouse embryo, which produces a protein (Crry), develops without damage inflicted by its mother's immune system.

In searching for a resolution, immunologists have sought out factors that might somehow suppress a mother's so-called acquired immunity, which sics T and B cells on "non-self" invaders, like a baby. But this form of immunity is only one of several cooperating systems. And it now seems that scientists have been looking in the wrong place.

Hector D. Molina and his colleagues at Washington University in St. Louis recently discovered that factors controlling innate immunity--an evolutionarily older and more primative arsenal than our acquired defenses--are essential for maintaining normal pregnancies in mice. They reported their work in the January 20th issue of Science.

Molina wasn't trying to tackle the pregnancy paradox when he started his work. Instead he was hoping to learn whether the murine gene, complement receptor-related gene Y (Crry), and its product Crry, helped protect the body from damage inflicted by inflammation. The swollen, hot, red splotches inflammation causes on the outside of the body speak of a cellular hell on the inside, where sundry immune cells attack and destroy infected or foreign tissues in a variety of ways.

One crucial tactic involves complement proteins that parachute down to foreign cells and, through a series of steps, tag them for destruction or eventually blast fatal holes through their membranes. Crry acts to prevent two complement proteins, C3 and C4, from marking foreign cells early on in the cycle.

Image: HECTOR D. MOLINA

ABNORMAL EMBRYO. A nine-day-old mouse embryo, which lacks a protective protein (Crry), is
being attacked by its mother's immune system.

Molina planned to further elucidate Crry's function in vivo by creating Crry knockout mice. He disrupted the genes in one group of animals and crossed them with healthy animals to form a generation of mice having one normal and one mutant copy of Crry. The group expected that at least a quarter of the offpring from these mice would inherit two mutant copies of Crry and so have no Crry protein regulation of C3 or C4.

Instead they found no Crry deficiency among the 245 births in their study. All of the animals inheriting two mutant copies of Crry had in fact died as embryos some 10 days after conception. Although Crry is not the only complement regulator, it appeared as though its absence was enough to leave an embryo vulnerable to its mother's complement system. Normal animals, they found, did express early on large amounts of Crry on fetal cells called trophoblasts--which help form the boundary between mother and child.

To shore up the argument, Molina also created mice that lacked both Crry and complement proteins. These animals gave birth to Crry-deficient but otherwise healthy pups--further proving that Crry served to protect normal developing embryos from their mother's immunity. No complement, no danger. "It appears that the mother has to constantly control complement activation, especially on the surface of the placenta, for an embryo to survive," Molina notes.

Crry exists only in rodents, but two substances--decay accelerating factor (DAF) and membrane cofactor protein (MCP)--serve a like purpose in people. And it is possible that DAF and MCP deficiencies might play a role in miscarriages. Molina's team plans to test this idea next, focusing on women who have suffered multiple miscarriage or have autoimmune diseases such as lupus erythematosus. "Using the mouse studies as a framework," Molina adds, "we can jump to human studies and see whether miscarriages in women also involve complement regulation." If they do, therapies to help certain women carry to term may not be far off.